Solution containing trimethoprim, sulfacetamide and polymyxin

ABSTRACT

Ophthalmic solution suitable for treatment of microbial, especially bacterial, infections of and around the eye containing sulfacetamide, a medicinally or pharmaceutically acceptable water soluble mono salt of trimethoprim, a medicinally or pharmaceutically acceptable water soluble salt of polymyxin, especially polymyxin B, and water, the solution having a pH in the range of 4.5 to 6.5 with 5 to 6 being preferred.

This is a continuation of application Ser. No. 428,918, filed on Dec.27, 1973, now abandoned.

BACKGROUND OF THE DISCLOSURE

The present invention relates to an aqueous ophthalmic preparation andmore particularly to an aqueous ophthalmic solution useful for treatingantimicrobial infections and particularly bacterial infections of andabout the eye.

In particular, the aqueous ophthalmic solution of this inventioncontains 2,4-diamino-5-(3',4',5'-trimethoxybenzyl) pyrimidine (known astrimethoprim), N'-Acetylsulfanilamide, sometimes calledp-aminobenzenesulfonacetamide, (hereinafter called sulfacetamide) andpolymyxin, preferably polymyxin B.

Trimethoprim is a well known antimicrobial agent and has foundparticular utility in the treatment of various bacterial and protozoalinfections, see U.S. Pat. No. 2,909,522. Trimethoprim has also been usedin the past in combination with various sulphonamides as a sulphonamidepotentiator.

Sulfacetamide is also a well known antimicrobial agent (see p. 13 of TheMerck Index, Eighth Edition, 1968) and has found particular utility inthe treatment of bacterial infections.

Polymyxin, a generic name for antibiotics (see p. 848 of The MerckIndex, Eighth Edition, 1968) is useful as an antimicrobial agent and hasparticularly useful activity in the treatment of gram-negative bacterialinfections.

During the last few years, it became apparent that a new and improvedbroad spectrum ophthalmic solution was needed for the treatment of themultitude of bacterial infections encountered in the eye.

A new solution in order to be useful as an antibacterial for ophthalmicuse had to remain stable for long periods of time (useful shelf life),not lose its potency (a known characteristic of polymyxin under certainconditions), remain as a clear solution, that is not discolor, e.g., asa result of oxidation of the sulphonamide (a known characteristic ofsulfacetamide base in solution), not form insoluble substances orcomplexes because of the combining of trimethoprim, a sulphonamide,and/or a polymyxin in the same solution (a known difficulty encounteredwith trimethoprim and certain sulphonamides), and also not be especiallyirritating to the eye (e.g., because of the pH of the solution, orbecause of the use of organic solvents which are not particularlyacceptable to the eye).

As a result of this invention there is provided an ophthalmic solutionmeeting the stringent criteria set forth above as well as a solutionhaving a broad spectrum antimicrobial, especially antibacterialactivity.

According to the present invention there is provided an aqueousophthalmic solution which has been discovered to meet the stringentcriteria set forth above, said ophthalmic solution containing (1)chemotherapeutic and especially antibacterial effective treatment amountof sulfacetamide in solution; (2) a water soluble, pharmaceuticallyacceptable effective sulfacetamide potentiating amount of mono salt oftrimethoprim, preferably a mono acid addition salt of trimethoprim, insolution; (3) a chemotherapeutic and especially an antibacterialeffective antibacterial treatment amount of a water solublepharmaceutically acceptable salt of polymyxin, especially polymyxin B,in solution; and (4) water, the solution having a pH in the range of 4.5to 6.5 with a pH of 5 to 6 being preferred.

In addition, the present invention may include isotonic agents such assodium chloride to make the solution isotonically compatable with thefluids of the eye as well as pharmaceutically or medicinally acceptablepH adjusting agents.

Further optional ingredients such as preservatives or viscosityincreasing and film forming agents to prolong mucus membrane contacttime, etc., may be included so long as they do not detrimentally effectthe desirable properties of the solution.

In accordance with this invention the ophthalmic solution contains fromabout 0.05 % to 0.66 % w/v of sulfacetamide (as base) with 0.10 to 0.50% w/v of sulphacetamide (as base) being preferred, from about 0.005 to1.0 % w/v of trimethoprim (as base) with 0.010 to 0.5 % w/v oftrimethorpim (as base) being preferred, from about 0.01 to 0.3% w/v ofpolymyxin (as base) with .05 to 0.15% w/v of polymyxin being preferred.The remainder of the solution is water although from about 0.02 to 1 %w/v of a pH adjusting agent may be incorporated therein with about 0.03%to 0.07% of a pH adjusting agent being preferred.

Substances which can be used as pharmaceutically or medicinallyacceptable acids to form water soluble pharmaceutically acceptable monosalts of trimethoprim are for example, pharmaceutically acceptablemineral acids such as sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, as well as pharmaceutically acceptable organic acids such aspharmaceutically acceptable carboxylic acids preferably having between 1to 20 carbon atoms and most preferably 1 to 10 carbon atoms; e.g.,tartaric, citric, lactic, embonic, salicyclic, glutamic, glutaric,naphthoic, acetic, and ethylenediamine-tetra acetic acid and otherpharmaceutically acceptable organic acids such as methane sulphonicacid. The acids used herein to form the salt or the salts oftrimethoprim potentiator must be stronger acids, i.e., have a lower pKathan the sulphonamide. At present, the preferred acids are lactic acid,or sulfuric acid, both being conveniently accessible and acceptable forthe practice of this invention.

The water soluble pharmaceutically acceptable salts of trimethoprim maybe formed by the reaction of trimethoprim and a pharmaceuticallyacceptable acid.

A pharmaceutically acceptable mono acid addition salt of trimethoprim ora mono acid addition salt of a pharmaceutically acceptable acid andtrimethoprim is defined herein as a salt consisting of mono-protonatedtrimethoprim and an anion of a pharmaceutically acceptable acid. The pHof the solution and the Pka's of the pharmaceutically acceptable acidand trimethoprim will determine their respective ionization status.Although it is well known that the chemotherapeutic, especially theantibacterial, activities of the sulphonamides and of trimethoprim aremutually enhanced when these agents are acting together, for thepurposes of this invention, trimethoprim is herein sometimes referred toas a sulfacetamide potentiator.

The present invention is not limited to a particular polymyxin andaccordingly all of the polymyxins disclosed on page 848 of The MerckIndex, 8th Edition, 1968, as well as pages 278 and 279 which disclosecolestin (polymyxin E), are incorporated herein by reference hereto,although for the purpose of this invention polymyxin B is preferred.

In the practice of this invention, the polymyxin is utilized as a watersoluble pharmaceutically acceptable or medicinally acceptable salt.Conveniently, the polymyxin may be used as a sulfate salt or ahydrochloric acid salt in the solution, e.g., polymyxin B sulfate.

The polymyxin as a salt may be conveniently dissolved in the solution atroom temperature without stirring although stirring may be used.

The sulfacetamide and trimethoprim as a salt may be convenientlydissolved in the solution at elevated temperatures of 85° to 90° C withstirring although lower temperatures may also be used. This may beaccomplished readily either by adding sulfacetamide to the water with orwithout the salt of trimethoprim present.

It is preferable to insure that the pH of the solution to which thesulfacetamide or the salt of trimethoprim is added in any order ismaintained at a volume and pH sufficient to prevent formation of aninsoluble salt.

Usually the ratio of sulfacetamide to trimethoprim as base or polymyxinas base, e.g., polymyxin B, useful to obtain a therapeutic effect (e.g.,to treat bacterial infections) is in the order of 5:1 (w/w), althoughratios being between 10:1 to 0.1:1 (w/w) are useful, and in certaincases it may be as high as between 20:1 to 0.1:1 (w/w).

In practice the preferred amounts of polymyxin per 100 ml. of solutionis about 500,000 to 2,000,000 units with about 1,000,000 to 1,200,000units being most preferred. 1,200,000 units of polymyxin representsabout .15 grams of polymyxin B in terms of base.

As noted previously, the pH of the solution is between 4 and 6.5 with arange of 4.5 to 5.5 being preferred and a pH of 5.0 ± 0.3 being mostpreferred to meet the criteria set forth herein.

Suitable pH adjusting agents which may be included in the solutioninclude the pharmaceutically acceptable acids previously mentioned suchas hydrochloric acid or under certain conditions may includepharmaceutically acceptable bases such as sodium hydroxide, potassiumhydroxide, etc.

The amount of pH adjusting agent normally used if needed would be fromabout 0.02 to 1.0 percent w/v with 0.03 percent to 0.07 percent beingpreferred.

As previously mentioned the solution may also contain isotonic agentssuch as sodium chloride with an amount in the range of 0.3 to 1.2grams/100 ml of solution being useful and with an amount between 0.6 to1.0 grams/100 ml of solution being preferred.

Other optional ingredients such as preservatives, e.g., THIMEROSAL madeby Eli Lilly and Company may also be included. In addition, viscosityand film forming agents such as Methocel 65 HG, 4000 cps may also beincluded to prolong contact of the solution with the mucous membrane.

It also may be desirable in certain cases to add local anaethesiacomponents or other ingredients to enhance stability if needed.

Accordingly, it should again be understood that other ingredients may beadded so long as these additional ingredients do not detract from thedesirable properties of the solution.

The quantity of the ophthalmic solution of this invention which can beadministered to a host mammal or animal, e.g., human, rabbit, etc., forthe treatment of microbial and especially bacterial infections variesaccording to the species of the host, its size, its age, generalcondition of health and severity and type of infection.

The solution of this invention would normally be packaged inconventional ophthalmic dispensing containers and would normally beadministered around the eye as 0.02 to 0.1 ml drops containing theingredients in the concentration set forth above.

Normally, one or two drops of the solution would be administered 1 to 4times daily. For example, in the treatment of bacterial infectionsaround the eye in man, animals, e.g., rabbits, (e.g., forconjunctivitis), from a solution containing 1 mg/ml of trimethoprimbase, 5 mg/ml of sulfacetamide, and 10,000 u/ml of polymyxin B as base,two 0.07 ml drops may be administered 2 to 4 times daily.

The solution of this invention has shown in invitro tests wideantibacterial inhibitory activity against various bacteria, normallyfound causing infections around the eye at dilutions of at least 1:300(which is likely to occur in the eye because of the eye fluids). Amongthe bacteria causing infections around the eye and in which inhibitoryactivity has been found are the following: St. pyogenes, Staph. aureus,N. gonorrhoeae, Morax. phenylpyrovich, Morax. nonliquifaciens, St.pneumoniea I, Ps. aeruginosa and H. influenzae.

In 12 month storage tests, with the solution of the invention,satisfactory potencies for all active ingredients has been observed at5° C and 25° C.

It should be understood that the ophthalmic solution of this inventionis sterile and that the water used in its preparation is preferablydistilled water.

As used herein the term infections of and around the eye is meant toinclude external bacterial infections of the eye, due to susceptibleorganisms and includes the following conditions: acute and chronicconjunctivitis, pinkeye, infected sockets, corneal ulcers, keratitis,episcleritis, blepharitis. The solution of the present invention is alsouseful as an adjunct to surgery in dacryocystitis; and prophylactically,before or after ophthalmic surgery and following serious eye injuries orremoval of foreign bodies.

The following examples further illustrate this invention. It is to benoted that all temperatures are in degrees centigrade, unless otherwisespecified and where no temperature is given for the mixing of theingredients or to prepare the salt, room temperature is the temperatureat which the ingredients were mixed or at which temperature the salt wasformed.

Obviously higher or lower temperatures may be used depending on howquickly it is desired for the mixing or the formation of the salt totake place as well known by those skilled in the art.

All percentages in this application mean w/v percentages, unlessotherwise specified.

EXAMPLE 1 Ophthalmic Solution

    ______________________________________                                        Sulfacetamide          0.50 g.                                                Trimethoprim Hemisulfate Monohydrate                                                                 0.123 g.                                                equivalent to                                                                Trimethoprim Base      0.10 g.                                                Polymyxin B Sulfate    1,200,000 u.(.15 g.)                                   Thimerosal - Preservative                                                                            0.001 g.                                               Sodium Chloride        0.83 g.                                                Water for Injection, q.s.                                                                            100.00 ml.                                             ______________________________________                                    

General Preparation

Added the polymyxin B sulfate to 10 ml. waer. Allowed it to dissolvewithout stirring.

In a separate container, dissolved the trimethoprim hemisulfatemonohydrate and sulfacetamide in 35 ml. water heated to 85° - 90° C.Added 35 ml. cold water. Mixed continuously. Added the sodium chloride.

To the preceding solution, added the polymyxin B sulfate solution.Rinsed container with 10 ml. water and added rinsing to bulk solution.Added THIMEROSAL. Brought solution to near final volume with water.Cooled solution to room temperature (25° C.). Checked pH and adjustedwith 2N sodium hydroxide solution to a pH of 5.0 ± 0.2.

Adjusted to final volume with water. Mixed for 10 minutes and recheckedpH. Passed solution through a suitable filter. Filled 10 ml. portions ofsolution into amber bottles. Applied suitable closures. Sterilizedbottles by autoclaving at 121° C. for 20 minutes.

Alternately, the solution may be sterilized by filtration through asuitable sterile filter and aseptically subdivided into sterile bottles.

EXAMPLE 2 Ophthalmic Solution

    ______________________________________                                        Sulfacetamide          0.50 g.                                                Trimethoprim Hemisulfate Monohydrate                                                                 0.123 g.                                                equivalent to                                                                Trimethoprim Base      0.10 g.                                                Polymyxin B Sulfate (includes 20%                                              overage)              1,200,000 u.(.15 g.)                                   Thimerosal             0.001 g.                                               Sodium Chloride        0.83 g.                                                Water for Injection, q.s.                                                                            100.00 ml.                                             ______________________________________                                    

General Preparation

Added the polymyxin B sulfate to 10 ml. water. Allowed drug to dissolvewithout stirring.

In a separate container, dissolved the trimethoprim hemisulfate and thesulfacetamide in 70 ml. water heated to 50° C. Added the sodiumchloride.

To the preceding solution, added the polymyxin B sulfate solution.Rinsed container with 10 ml. water and added rinsing to bulk solution.Added the THIMEROSAL. Brought solution to near final volume with water.Cooled solution to room temperature (25° C.).

Checked pH and adjusted with 2N sodium hydroxide solution to a pH of 5.0± 0.2.

Adjusted to final volume with water. Mixed for 10 minutes and recheckedpH. Passed solution through a suitable filter. Filled 10 ml. portions ofsolution into amber bottles. Applied closures. Sterilized containerswith steam under pressure at 121° C. for 20 minutes.

NOTE: Under General Preparation, water refers to water for injection.

EXAMPLE 3 Ophthalmic Solution

    ______________________________________                                        Sulfacetamide          0.05 g.                                                Trimethoprim Lactate equivalent to                                                                   0.01 g.                                                 trimethoprim base                                                            Polymyxin B Sulfate (includes 20% excess)                                                            1,200,000 u.(.15 g.)                                   Water for Injection, q.s.                                                                            100.00 ml.                                             ______________________________________                                    

EXAMPLE 4 Ophthalmic Solution

    ______________________________________                                        Sulfacetamide          0.50 g.                                                Trimethoprim Lactate equivalent to                                                                   0.10 g.                                                 trimethoprim base                                                            Polymyxin B Sulfate (includes 20% excess)                                                            1,200,000 u.(.15 g.)                                   Water for Injection, q.s.                                                                            100.00 ml.                                             ______________________________________                                    

EXAMPLE 4 ophthalmic Solution

    ______________________________________                                        Sulfacetamide          0.50 g.                                                Trimethoprim Lactate   0.130 g.                                                equivalent to                                                                Trimethoprim Base      0.10 g.                                                Polymyxin B Sulfate (includes 20%                                              excess)               1,200,000 u.(.15 g.)                                   Water for Injection, q.s.                                                                            100.00 ml.                                             ______________________________________                                    

We claim:
 1. A clear aqueous pharmaceutically acceptable solutioncapable for use as an ophthalmic antibacterial preparation, the solutionbeing at a pH of 4.0 to 6.5 and the solution containing 0.05 to 0.66 %w/v of sulfacetamide, 0.01 to 0.50% w/v of trimethoprim in the form of apharmaceutically acceptable water soluble salt, and 0.01 to 3% w/v ofpolymyxin in the form of a pharmaceutically acceptable water solublesalt and water.
 2. A solution according to claim 1 in which thepolymyxin is polymyxin B.
 3. A solution according to claim 1 in whichthe polymyxin is polymyxin E.
 4. A method of treating bacterialinfections of and around the eye of a patient which comprisesadministering to the patient an effective antibacterial treatment amountof the solution of claim
 1. 5. A method according to claim 4 in whichthe patient is a mammal.
 6. A method according to claim 5 in which thepatient is a human.
 7. A method according to claim 6 in which thepolymyxin is polymyxin B.
 8. A solution according to claim 1 in whichthe pH of the solution is about 4.5 to 5.5.
 9. A solution according toclaim 1 in which the pH of the solution is about 5.0 ± .3.
 10. Thesolution of claim 8 in which the polymyxin is polymyxin B.